17{60 -alkanoyloxy-11{62 -methyl-19-norpregna-4,6-diene-3,20-diones and the 6{60 -chloro-19-norpregn-4-ene-3,20-diones corresponding

ABSTRACT

17 Alpha -Alkanoyloxy-11 Beta -methyl-19-norpregn-4-ene-3,20diones are converted to the corresponding enol ethers by standard methods and the latter derivatives are, alternatively, oxidized to yield the corresponding 4,6-diene-3,20-diones or are contacted first with an N-chloroamide or N-chloroimide, e.g., Nchlorosuccinimide, then with a strong mineral acid to yield the 6 Alpha -chloro compounds. Reaction of the aforementioned 4,6diene-3,20-diones with a peracid results in the corresponding 6 Alpha ,7 Alpha -epoxy-3-keto- Delta 4 compounds, which are contacted with a hydrogen halide, and the resulting 6 Beta chloro-7 Alpha -hydroxy compounds are dehydrated by conversion first to the 7-methanesulfonate followed by heating with a suitable base to provide the desired 6-chloro-3-keto- Delta 4,6 derivatives. The compounds of this invention are unusually potent progestational and estrogen-inhibitory agents.

United States Patent 15] 3,682,986 Baran et al. [451 Aug. 8, 1972 [54] 17a-ALKANOYLOXY-l lB-METHYL- 19- Primary Examiner-Henry A. French NORPREGNA-4,6-DIENE-3,20-DIONES AND THE 6a-CHLORO-l9-NORPREGN- 4-ENE-3,20-DIONES CORRESPONDING Inventors: John S. Baran, 9320 Marmora, Morton Grove; Ivar Laos, 8419 East Prairie Road, Skokie, both of Ill.

Filed: June 11, 1970 Appl. No.: 45,592

us. Cl ..'...26o 397.4s, 260/239 .55 R

Int. Cl ..C07c 169/34 Field of Search ..Machine Searched Steroids References Cited UNITED STATES PATENTS 5/1966 Wettstein et a1 ..260/397.l

Attorney-John M. Brown, John J. Kolano, Elliot N. Schubert, Lowell C. Bergstedt, Sybil Meloy, Walter C. Ramm and Helmuth A. Wegner 57 ABSTRACT I 7a-Alkanoyloxy-l lB-methyll9-norpregn-4-ene- 3,20diones are converted to the corresponding enol ethers by standard methods and the latter derivatives are, alternatively, oxidized to yield the corresponding 4,6-diene-3,20-diones or are contacted first with an N- chloroamide or N-chloroimide, e.g., N-chlorosuccinimide, then with a strong mineral acid to yield the 601- chloro compounds. Reaction of the aforementioned 4,6-diene-3,20-diones with a peracid results in the corresponding 6oz,7az-epoxy-3-keto-A compounds, which are contacted with a hydrogen halide, and the resulting 6B-chloro-7a-hydroxy compounds are dehydrated by conversion first to the 7-methanesulfonate followed by heating with a suitable base to provide the desired 6-chloro-3-keto-A" derivatives. The compounds of this invention are unusually potent progestational and estrogen-inhibitory agents.

7 Claims, No Drawings wherein R is an alkanoyl radical possessing one to carbon atoms, e.g. methyl, ethyl, propyl, and the like, R is a lower alkyl radical of one to four carbon atoms, the dotted line indicates an optional 6(7) double bond,

X is a-chloro when the 6(7) linkage is saturated and X 2 is hydrogen or chloro when the 6(7) linkage is unsaturated.

The novel compounds of this invention are conveniently produced by utilizing as starting materials the 3-keto-A substances of the following formula the manufacture of which is described in our copending application 803,077, filed-Feb. 27, 1969 now US. Pat. No. 3,527,778. In that formula R is as defined hereinbefore.

The 6-dehydro compounds of the present invention are conveniently obtained by oxidation of the corresponding 3,5-diene enol ethers, which are altematively produced from the corresponding A -3-ketones or the A enol ethers. These alternate processes are exemplified by the isomerization and deketalization of 1 7a-hydroxy-3-methoxy-l l B-methyll9-norpregna- 2,5( l0)-dien-20-one -ethylene ketal by means of ptoluenesulfonic acid to yield 17a-hydroxy-3-methoxyl l B-methyll 9-norpregna-3,5-dien-20-one and the reaction of l 7a-acetoxy-l lB-methyll 9-norpregn-4- ene-3,20-dione with ethyl orthoformate and ptoluenesulfonic acid to yield l7a-acetoxy-3-ethoxyl l B-methyll9-norpregna-3,5-dien-20-one. Oxidation of those enol ethers with manganese dioxide in benzene affords l 7a-hydroxy-l lB-methyll 9-norpregna-4,6- diene-3,20-dione and l7a-acetoxy-l lB-methyl-l9-norpregna-4,6-diene-3,20-dione, respectively.

A preferred method for the manufacture of the instant 6-chloro-6-dehydro compounds utilizes the corresponding 6-dehydro substances as starting materials.

As a specific'example, l7a-acetoxy-1lB-methyl-l9- norpregna-4,6-diene-3,20-dione in methylene chloride is epoxidized, typically with monoperphthalic or mchloroperbenzoic acid, to afford l7a-acetoxy-6a,7aepoxy-l l B-methyl- 19-norpregn-4-ene-3 ,20-dione. Cleavage of that epoxide by means of hydrogen chloride and dioxane results in l7a-acetoxy-6B-chloro- 7a-hydroxy-l l B-methyl- 1 9-norpregn-4-ene-3 ,20- dione. Formation of the 7-methanesulfonate is accomplished by reaction of that chlorohydrin with methanesulfonyl chloride in pyridine at 0 and that ester is heated in dirnethylforrnarnide with sodium acetate at about to afford l7a-acetoxy-6-chlorol lB-methyll 9-norpregna-4,6-diene-3 ,20-dione.

The instant 6a-chloro derivatives are conveniently obtained by treating the aforementioned 3-enol ethers with hypochlorous acid or a reagent capable of liberating that acid. Other suitable reagents include alkali metalsalts of hypochlorous acid or N-chloroamides or N-chloroimides, e.g. N-chlorosuccinimide, in the presence of sodium acetate, acetic acid and water, preferably at temperatures near 0 for periods up to several hours. The hypochlorous acid treatment provides the corresponding 6fi-2-chloro-3-keto-A deriva- 5 tive, which upon subsequent strong mineral acid epimerization under anhydrous conditions yields the desired Got-chloro derivative. Preferably, acid treatment is employed upon the compound dissolved in an organic acid such as acetic acid. Suitable strong mineral acids include dry hydrogen chloride. The reaction time can be in the range of several hours. Preferred temperatures are between 5 and 20 C.

The instant compound wherein the l3B -alkyl group contains more than one carbon atom are obtained as dlmixtures. Resolution of those dl-compounds to afford the individual d and l enantiomorphs is conveniently effected by esterification of an hydroxy group with a dibasic acid anhydride such as succinic or phthalic anhydride to afiord the corresponding acid ester, which is resolved by means of an optically active amine such as brucine, morphine, quinine, quinidine, strychnine, etc.

The compounds of this invention are useful as a result of their valuable pharmacological properties. As indicated hereinbefore they are potent progestational and estrogen-inhibitory agents.

The assay used for determination of progestational activity is a modification of that described by Clauberg, C. Zentr. GynakoL, 54, 2757 (1930) and later in Hormone Assay, C. W. Emmens, Academic Press, page 422 1950). The modified assay is described as follows:

Female rats weighing about 1 kg. are primed daily for 6 days with 5 mcg. subcutaneous injections of estradiol 17B). Starting on the day following the last priming injection the test compound, dissolved or suspended in corn oil, is administered subcutaneously each day for a period of 5 days. A control group of animals is treated with corn oil alone. On the day after the last treatment, the animals aresacrificed; a segment of the uterus is taken for histological examination and the degree of arborization of the endometrial glands is graded by the method described by McPhail, M. K., J. PhysioL, 83, (1934). The progestational responses are rated on a scale from 1 to 4, a response of at least 2 being required for a compound to be rated active.

The estrogen-inhibitory property of the compounds of this invention is detected by the assay described by Edgren and Calhoun, Proc. Soc. Exp. Biol. Med, 94, 537 195 7), the details of which assay are as follows:

Groups of 8-10 immature female mice are injected once daily for a period of 3 days with 0.1 ml. of a corn oil solution containing 0.1 mcg. of estrone together with one-third of the selected dose of the test compound. Twenty-four hours after the final injection the animals are sacrificed and their uteri are removed, cleaned and weighed. The uterine weights are compared with those of a similar group of control animals receiving injections of corn oil containing the same dose of estrone alone. A compound is designated active if it produces a uterine response significantly smaller (P 2 0.01) than control values. Potency is expressed in terms of percentage of the activity of the standard, i.e. progesterone.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited thereby either in spirit or in scope as many modifications both in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees Centigrade (C.) Quantities of materials are expressed in parts by weight unless otherwise noted.

EXAMPLE 1 To a solution of 2,3 parts of 17a-acetoxy-l 1,8- methyl-l9-norpregn-4-ene-3,20-dione in 22 parts of, dioxane is added 0.18 part of ethanol, 2.12 parts of ethyl orthoformate and a solution of 0.11 part of ptoluenesulfonic acid monohydrate in 1.8 parts of dioxane. The resulting reaction mixture is stirred at room temperature for about 1 A hours, then is neutralized by the addition of 1.8 parts of pyridine. The mixture is then concentrated under reduced pressure until crystallization of the produce commences. Benzene is added and the resulting solution is washed several times with water, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting crude product is azeotropically distilled with xylene to remove traces of ethyl orthoformate, thus affording crystalline l7a-acetoxy-3-ethoxy-11B- methyl- 1 9-norpregna-3 ,5-dien-20-one, characterized by nuclear magnetic resonance peaks at about 44, 58, 64, 71, 78, 85, 122, 125, 217, 224, 231, 238 and 316 cycles per second.

EXAMPLE 2 The substitution of an equivalent quantity of l7a-nbutyryloxyl l ,B-methyl- 1 9-norpregn-4-ene-3,20-dione in the procedure of Example 1 results in l7a-n-butyryloxy-3-ethoxy-l lB-methyl-19-norpregna-3,5-dien- 20-0ne.

EXAMPLE 3 To a solution of 2.4 parts of 17a-acetoxy-3-ethoxyl 1 B-methyll9-norpregna-3,5-dien-20-one in 140 parts of benzene is added 12 parts of manganese dioxide and the resulting reaction mixture is stirred at room temperature for about 45 minutes. The oxidant is then removed by filtration and the filtrate is concentrated to dryness under reduced pressure. The resulting crude product is purified by adsorption on a silica gel chromatographic column followed by elution with 7 percent ethyl acetate in benzene and purification of the eluted fraction by recrystallization from acetone-hexane, thus affording 1 7a-acetoxy- 1 lBmethyll 9-norpregna-4 ,6- diene-3,20-dione, melting at about 206208. It is characterized further by an ultraviolet absorption maximum at about 282.5 millimicrons with a molecular extinction coefiicient of about 25,300 and also by the following structural formula o In EXAMPLE 4 When an equivalent quantity of l7oz-n-butyryloxy-3- ethoxy-l lB-methyl-19-norpregna-3,5-dien-20-one is substituted in the procedure of Example 3, there is obtained l7a-n-butyryloxy-l l B-methyll 9-norpregna-4,6 -diene-3,20-dione.

EXAMPLE 5 A mixture containing 5 parts of 17a-acetoxy-3- ethoxy-l IB-methyl- 1 9-norpregna-3 ,5 -dien-20-one, 3 parts of anhydrous sodium acetate, parts of acetone and 30 parts of water is cooled to 05, at the end of which time 6.4 parts of N-chlorosuccinimide and 2 parts of glacial acetic acid are added. The mixture is stirred for 30 minutes at a temperature of 0-5, then is diluted with 300 parts of water and stored at 05 for about 16 hours. The precipitate which forms is collected by filtration, washed on the filter with water and dried in air, then purified by recrystallization from acetone to yield l7a-acetoxy-6B-chloro-l lB-methyl- 19-norpregn-4-ene-3,20-dione.

A slow stream of dry hydrogen chloride is introduced into a suspension of 3 parts of the aforementioned product and 50 parts of glacial acetic acid while the temperature is maintained below 10. After about 1 hour the reaction mixture is poured into parts of water containing 35 parts of potassium acetate and the resulting mixture is cooled. The precipitate which forms is collected by filtration, washed with water, then dried and recrystallized from a mixture of acetone and hexane to yield l7a-acetoxy-6a-chloro-1lB-methyl- 19-norpregn-4-ene-3,20-dione, characterized by infrared absorption maxima in chloroform at about 5.76, 5.82, 5.94 and 6.18 microns and also by the following structural formula EXAMPLE 6 When an equivalent quantity of 17a-n-butyryloxy-3- ethoxy- 1 l B-methyl- 1 9-norpregna-3 ,5-dien--one is substituted in the successive processes of Example 5, there are obtained l7a-n-butyryloxy-6fl-chloro-l 1B- methyl- 1 9-norpregn-4-ene-3 ,20-dione and 1 7a-n-butyryloxy-6a-chloro-l l B-methyll 9-norpregn-4-ene- 3,20-dione.

EXAMPLE 7 A solution of 2.5 parts of l7a-acetoxy-l lB-methyl- 19-norpregna-4,6-diene-3,20-dione in about 200 parts of methylene chloride is treated with 125 parts by volume of a 5 percent solution of monoperphthalic acid in ether and the resulting mixture is kept at room temperature for about 24 hours, then is washed successively with 5 percent aqueous sodium carbonate and water, dried over anhydrous sodium sulfate and concentrated to the point of incipient crystallization. That mixture is then cooled until crystallization is complete and the resulting precipitate is collected by filtration and dried in air. Purification of that product by chromatography on silica gel affords 17a-acetoxy-l1B-methyl-6oz,7aepoxy-l9-norpregn-4-ene-3,ZO-dione, which displays an ultraviolet absorption maximum at about 241 millimicrons with a molecular extinction coefficient of about 15,400.

EXAMPLE 8 Method A,

A solution of 2 parts of the above prepared 611,70:- epoxy compound in 105 parts of acetic acid is treated with 6 parts of concentrated hydrochloric acid and the resulting mixture is kept at room temperature for about 6 hours. The product which precipitates upon dilution with water is collected by filtration, then purified by recrystallization from acetone-hexane, thus afiording l 7a-acetoxy-6-chlorol l B-methyl- 1 9-norpregna-4,6- diene-3,20-dione, melting at about l80-l82 and characterized also by infrared absorption maxinia, in chloroform at about 5.78, 5.83, 6.02, 6.23, and 6.30 microns. It displays an ultraviolet absorption maximum at about 282.5 millimicrons with a molecular extinction coefficient of about 20,900 and is represented by the following structural formula Method B A solution containing 1 part of l7a-acetoxy-l 1,8- methyl-6a,7a-epoxy-l9-norpregn-4-ene-3,20-dione dissolved in parts by volumeof a dioxane solution '1 N in hydrogen chloride is stored at room temperature for about 30 minutes, then is poured carefully into 300 parts by volume of a mixture of ice and water containing 8.4 parts of sodium bicarbonate. The resulting aqueous mixture is extracted with benzene and the benzene layer is separated, washed several times with water, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting product is l7a-acetoxy-6B-chloro-7B-hydroxypregn-4-ene-3,20-dione, obtained as a solid foam.

The latter chlorohydrin is dissolved in 12 parts of pyridine and the resulting mixture is placed in a nitrogen atmosphere and cooled to 0-5. To that mixture is then added 0.9 part by volume of methane-sulfonyl chloride and the reaction mixture is kept at 05 for about 18 hours. At the end of that time it is poured into a mixture of ice and water with stirring and the precipitate which forms is collected by filtration and washed on the filter with water, thus affording 17aacetoxy-6,8-chloro-7a-methanesulfonyloxypregn-4- ene-3,20-dione.

A mixture containing 1 part of the latter mesylate, 3.6 parts of anhydrous sodium acetate and 18 parts of dimethyl formamide is stirred in a nitrogen atmosphere at 8090 for about minutes, then is cooled and poured into a mixture of ice and water. The precipitate which forms is collected by filtration, washed with water and purified by chromatography on silica gel. The 2 percent ethyl acetate in benzene eluates are combined, then distilled to dryness, and the resulting solid product is purified by recrystallization from acetone-hexane to afford l7a-acetoxy-6-chloro-1IB- methyl- 1 9-norpregna-4,6-diene-3 ,20-dione, identical with the product of Method A.

EXAMPLE 9 When an equivalent quantity of l7a-n-butyryloxy-l l ,B-methyl-l9-norpregna-4,6-diene-3,20-dione is substituted in the successiveprocesses of Example 7, there are obtained l7a-n-butyryloxy-1 lB-methyl-6a,7aepoxy-l9-norpregn-4-ene-3,20-dione and 17a-n-butyryloxy-6-chloro-1 l B-methyll 9-norpregna-4,6- diene-3,20-dione.

What is claimed is:

1. A compound of the formula wherein R represents an alkanoyl radical of one to 10.

wherein R represents an alkanoyl radical of one to 10 carbon atoms.

3. A compound of the formula wherein R represents an alkanoyl radical of one to 10 carbon atoms.

4. A compound of the formula 

2. A compound of the formula
 3. A compound of the formula
 4. A compound of the formula
 5. The compound according to claim 1 which is 17 Alpha -acetoxy-11 Beta -methyl-19-norpregna-4,6-diene-3,20-dione.
 6. The compound according to claim 1 which is 17 Alpha -acetoxy-6 Alpha -chloro-11 Beta -methyl-19-norpregn-4-ene-3,20-dione.
 7. The compound according to claim 1 which is 17 Alpha -acetoxy-6-chloro-11 Beta -methyl-19-norpregna-4,6-diene-3,20-dione. 